1. Field of the Invention
This invention provides a method of improving glutathione (GSH) concentrations, both intra and extra-cellularly, in mammals, thereby improving the cellular and humoral immune response. It comprises oral administration of a therapeutically effective amount of nutritional supplement which is composed of critical and synergistic quantities of amino acids, peptides, and bioflavanoids.
2. Brief Description of Related Art
Glutathione is a well-known tripeptide, which exists in two basic forms. The antioxidant form or "reduced glutathione" tripeptide is conventionally called "glutathione" and abbreviated as "GSH". The oxidized form is a sulfur-sulfur linked compound known as glutathione disulfide (GSSG).
Glutathione in its biologically active, reduced form (GSH) has the formula: ##STR1##
and is appropriately named .gamma.-L-Glutamyl-L-cysteinylglycine. It is ubiquitous in animals, plants, and microorganisms and being water soluble is found mainly in the cell cytosol and other aqueous phases of the living system. Glutathione often attains millimolar levels inside living cells, which makes it one of the most highly concentrated intracellular antioxidants.
Glutathione is homeostatically controlled, both inside the animal cell and outside. Enzyme systems synthesize it, utilize it, and regenerate it per the gamma-glutamyl cycle. (Meister A. Glutathione, Ascorbate and Cellular Protection Cancer Res (Suppl) 1994 (Apr 1); 54:1969S-1975S).
Glutathione is most concentrated in the mammal liver (10 mM), where the P450 Phase II" enzymes require it to convert fat-soluble substances into water-soluble GSH conjugates in order to facilitate their excretion. While providing GSH for their specific needs, the liver parenchymal cells export GSH to the outside, where it serves as systemic source of-SH/reducing power.
Briefly, glutathione synthesis occurs within animal cells in two closely linked enzymatically controlled reactions that utilize Adenosine Triphosphate (ATP) and draw on nonessential amino acids as substrates. First, cysteine and glutamate are combined (by the enzyme gamma-glutamyl cysteinyl synthetase, with availability of cysteine usually being the rate-limiting factor. Cysteine is generated from the essential amino acid methionine, from the degradation of dietary protein, or from turnover of endogenous proteins. The buildup of GSH acts to feedback-inhibit this enzyme, thereby helping to ensure homeostatic control over GSH synthesis.
The second GSH synthesis reaction combines gamma-glutamylcysteine with glycine to generate GSH (catalyzed by GSH synthetase).
With regard to the essentiality of GSH for the survival of the mammal, substantial information is available from studies on hereditary GSH depletion in the human, and from experimental depletion and repletion of GSH in animal models and cell cultures, see for example: Meister A. Larsson A. Glutathione Synthetase Deficiency and Other Disorders of the Gamma-Glutamyl Cycle; Scriver CR. et al eds. The Metabolic and Molecular Bases of Inherited Disease (Volume I). New York: McGraw-Hill: 1995:1461-1495 (Chapter 43); and Beutler E. Nutritional and Metabolic Aspects of Glutathione, Annu Rev Nutr 1989;9:287-302.
Reduced GSH levels in mammalian cells are associated with a wide variety of pathophysiologic states, including hepatic dysfunction, malignancies, HIV infection, pulmonary disease, Parkinson's disease, related immunologic illnesses and physiological conditions; see for example the descriptions in Kidd, Alternative Medicine Review, Vol. 2, No. 3, pages 156-176 (1997).
The consequences of sustained GSH depletion are fatal. As cellular GSH is depleted, first individual cells die in those areas most affected. Then zones of tissue damage begin to appear. Localized free-radical damage spreads across the tissue in an ever-widening, self-propagating wave.
An object of this invention is to promote gastrointestinal absorption and intracellular uptake of components which will maximize intracellular reduced glutathione production by a mammal including a human.